MRI-Detected Brain Lesions and Cognitive Function in Patients With Atrial Fibrillation Undergoing Left Atrial Catheter Ablation in the Randomized AXAFA-AFNET 5 Trial.

BACKGROUND: We aimed to assess the prevalence of ischemic brain lesions detected by magnetic resonance imaging and their association with cognitive function 3 months after first-time ablation using continuous oral anticoagulation in patients with paroxysmal atrial fibrillation (AF). METHODS: We performed a prespecified analysis of the AXAFA-AFNET 5 trial (Anticoagulation Using the Direct Factor Xa Inhibitor Apixaban During Atrial Fibrillation Catheter Ablation: Comparison to Vitamin K Antagonist Therapy), which randomized 674 patients with AF 1:1 to uninterrupted apixaban or vitamin K antagonist therapy before first-time ablation. Brain magnetic resonance imaging using fluid-attenuated inversion recovery and high-resolution diffusion-weighted imaging was obtained within 3 to 48 hours after AF ablation in all eligible patients enrolled in 25 study centers in Europe and the United States. Patients underwent cognitive assessment 3 to 6 weeks before ablation and 3 months after ablation using the Montreal Cognitive Assessment (MoCA). RESULTS: In 84 (26.1%) of 321 patients with analyzable magnetic resonance imaging, high-resolution diffusion-weighted imaging detected at least 1 acute brain lesion, including 44 (27.2%) patients treated with apixaban and 40 (24.8%) patients treated with vitamin K antagonist (P=0.675). Median MoCA score was similar in patients with or without acute brain lesions at 3 months after ablation (28 [interquartile range (IQR), 26-29] versus 28 [IQR, 26-29]; P=0.948). Cerebral chronic white matter damage (defined as Wahlund score ≥4 points) detected by fluid-attenuated inversion recovery was present in 130 (40.5%) patients and associated with lower median MoCA scores before ablation (27 [IQR, 24-28] versus 27 [IQR, 25-29]; P=0.026) and 3 months after ablation (27 [IQR, 25-29] versus 28 [IQR, 26-29]; P=0.011). This association was no longer significant when adjusted for age and sex. Age was associated with lower MoCA scores before ablation (relative risk, 1.02 per 10 years [95% CI, 1.01-1.03]) and 3 months after ablation (relative risk, 1.02 per 10 years [95% CI, 1.01-1.03]). CONCLUSIONS: Chronic white matter damage as well as acute ischemic lesions detected by brain magnetic resonance imaging were found frequently after first-time ablation for paroxysmal AF using uninterrupted oral anticoagulation. Acute ischemic brain lesions detected by high-resolution diffusion-weighted imaging were not associated with cognitive function at 3 months after ablation. Lower MoCA scores before and after ablation were associated only with older age, highlighting the safety of AF ablation on uninterrupted oral anticoagulation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02227550.

Reversibility of Diffusion-Weighted Imaging Lesions in Patients With Ischemic Stroke in the WAKE-UP Trial.

BACKGROUND: Reversibility of the diffusion-weighted imaging (DWI) lesion means that not all of the DWI lesion represents permanently injured tissue. We investigated DWI reversibility and the association with thrombolysis, reperfusion and functional outcome in patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke). METHODS: In this retrospective analysis of WAKE-UP, a randomized controlled trial (RCT) between September 2012 and June 2017 in Belgium, Denmark, France, Germany, Spain and United Kingdom, a convolutional neural network segmented the DWI lesions (b=1000 s/mm2) at baseline and follow-up (24 hours). We calculated absolute and relative DWI reversibility in 2 ways: first, a volumetric (baseline volume-24-hour volume >0) and second, a voxel-based (part of baseline lesion not overlapping with 24-hour lesion) approach. We additionally defined relative voxel-based DWI-reversibility >50% to account for coregistration inaccuracies. We calculated the odds ratio for reversibility according to treatment arm. We analyzed the association of reversibility with excellent functional outcome (modified Rankin Scale score of 0-1), in a multivariable model. RESULTS: In 363 patients, the median DWI volume was 3 (1-10) mL at baseline and 6 (2-20) mL at follow-up. Volumetric DWI reversibility was present in 19% (69/363) with a median absolute reversible volume of 1 mL (0-2) or 28% (14-50) relatively. Voxel-based DWI reversibility was present in 358/363 (99%) with a median absolute volume of 1 mL (0-2), or 22% (9-38) relatively. In 18% of the patients (67/363), relative voxel-based DWI reversibility >50% was present. Volumetric DWI reversibility and relative voxel-based DWI reversibility >50% was more frequent in patients treated with alteplase versus placebo (OR, 1.86 [95% CI, 1.09-3.17] and OR, 2.03 [95% CI, 1.18-3.50], respectively). Relative voxel-based DWI reversibility >50% was associated with excellent functional outcome (OR, 2.30 [95% CI, 1.17-4.51]). CONCLUSIONS: Small absolute volumes of DWI reversibility were present in a large proportion of randomized patients in the WAKE-UP trial. Reversibility was more often present after thrombolysis.

Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57-0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60-1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (P=0.443) or any hemorrhagic transformation (P=0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19-4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80-4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01525290.

Reproducibility of cerebral perfusion measurements using BOLD delay.

BOLD delay is an emerging, noninvasive method for assessing cerebral perfusion that does not require the use of intravenous contrast agents and is thus particularly suited for longitudinal monitoring. In this study, we assess the reproducibility of BOLD delay using data from 136 subjects with normal cerebral perfusion scanned on two separate occasions with scanners, sequence parameters, and intervals between scans varying between subjects. The effects of various factors on the reproducibility of BOLD delay, defined here as the differences in BOLD delay values between the scanning sessions, were investigated using a linear mixed model. Reproducibility was additionally assessed using the intraclass correlation coefficient of BOLD delay between sessions. Reproducibility was highest in the posterior cerebral artery territory. The mean BOLD delay test-retest difference after accounting for the aforementioned factors was 1.2 s (95% CI = 1.0 to 1.4 s). Overall, BOLD delay shows good reproducibility, but care should be taken when interpreting longitudinal BOLD delay changes that are either very small or are located in certain brain regions.

Sex differences in imaging and clinical characteristics of patients from the WAKE-UP trial.

BACKGROUND AND PURPOSE: Sex-based differences in acute ischemic stroke are a well-known phenomenon. We aimed to explore these differences between women and men in the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial. METHODS: We compared baseline demographic and imaging characteristics (visual fluid-attenuated inversion recovery [FLAIR] positivity, relative FLAIR signal intensity, collateral status) between women and men in all screened patients. In randomized patients (i.e., those with diffusion-weighted imaging (DWI)-FLAIR mismatch), we evaluated a modifying role of sex on the treatment effect of alteplase in multivariable logistic regression, with treatment adjusted for National Institute of Health Stroke Scale (NIHSS) score and age. Dependent variables were modified Rankin Scale (mRS) score of 0-1 at 90 days and distribution of mRS scores at 90 days. RESULTS: Of 1362 screened patients, 529 (38.8%) were women. Women were older than men, had higher baseline NIHSS scores and smoked less frequently. FLAIR positivity of the DWI lesion was equally present in women (174/529, 33.1%) and men (273/833, 33.3%; p = 1.00) and other imaging variables also did not differ between the sexes. In a total of 503 randomized patients, of whom 178 were women (35.4%), sex did not modify the treatment effect of alteplase on mRS score 0-1 or on the total distribution of mRS scores. CONCLUSION: As in many other stroke trials, more men than women were included in the WAKE-UP trial, but the presence of a visual DWI-FLAIR mismatch and the relative FLAIR signal intensity did not differ between the sexes. The treatment effect of alteplase was not modified by sex.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Detection of brain lesions after catheter ablation depends on imaging criteria: insights from AXAFA-AFNET 5 trial.

AIMS: Left atrial catheter ablation is well established in patients with symptomatic atrial fibrillation (AF) but associated with risk of embolism to the brain. The present analysis aims to assess the impact of diffusion-weighted imaging (DWI) slice thickness on the rate of magnetic resonance imaging (MRI)-detected ischaemic brain lesions after ablation. METHODS AND RESULTS: AXAFA-AFNET 5 trial (NCT02227550) participants underwent MRI using high-resolution (hr) DWI (slice thickness: 2.5-3 mm) and standard DWI (slice thickness: 5-6 mm) within 3-48 h after ablation. In 321 patients with analysable brain MRI (mean age 64 years, 33% female, median CHA2DS2-VASc 2), hrDWI detected at least one acute brain lesion in 84 (26.2%) patients and standard DWI in 60 (18.7%; P < 0.01) patients. High-resolution diffusion-weighted imaging detected more lesions compared to standard DWI (165 vs. 104; P < 0.01). The degree of agreement for lesion confirmation using hrDWI vs. standard DWI was substantial (κ = 0769). Comparing the proportion of DWI-detected lesions, lesion distribution, and total lesion volume per patient, there was no difference in the cohort of participants undergoing MRI at 1.5 T (n = 52) vs. 3 T (n = 269). CONCLUSION: The pre-specified AXAFA-AFNET 5 sub-analysis revealed significantly increased rates of MRI-detected acute brain lesions using hrDWI instead of standard DWI in AF patients undergoing ablation. In comparison to DWI slice thickness, MRI field strength had a no significant impact in the trial. Comparing the varying rates of ablation-related MRI-detected brain lesions across previous studies has to consider these technical parameters. Future studies should use hrDWI, as feasibility was demonstrated in the multicentre AXAFA-AFNET 5 trial.

Diffusion-Weighted Imaging and Fluid-Attenuated Inversion Recovery Quantification to Predict Diffusion-Weighted Imaging-Fluid-Attenuated Inversion Recovery Mismatch Status in Ischemic Stroke With Unknown Onset.

BACKGROUND: Visual rating of diffusion-weighted imaging (DWI)-fluid-attenuated inversion recovery (FLAIR) mismatch can be challenging. We evaluated quantification of DWI and FLAIR to predict DWI-FLAIR mismatch status in ischemic stroke. METHODS: In screened patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke), we retrospectively studied relative DWI (rDWI SI) and FLAIR signal intensity (rFLAIR SI). We defined the optimal mean rFLAIR SI and interquartile range of the rDWI SI in the DWI lesion to predict DWI-FLAIR mismatch status. We investigated agreement between each quantitative parameter and the DWI-FLAIR mismatch and the association between both quantitative parameters. We evaluated the predictive value of the quantitative parameters for excellent functional outcome by logistic regression, adjusted for DWI lesion volume, treatment, age, and National Institutes of Health Stroke Scale score. RESULTS: In the rFLAIR and rDWI SI analysis, 213/369 and 241/421 subjects respectively had a DWI-FLAIR mismatch. A mean rFLAIR SI cutoff of 1.09 and interquartile range rDWI SI cutoff of 0.47 were optimal to predict the DWI-FLAIR mismatch with a sensitivity and specificity of 77% (95% CI, 71%-83%) and 67% (95% CI, 59%-74%), and 76% (95% CI, 70%-81%) and 72% (95% CI, 65%-79%), respectively. For both quantitative parameters, agreement with the DWI-FLAIR mismatch was fair (73%, κ=0.44 [95% CI, 0.35-0.54] for rFLAIR and 74%, κ=0.48 [95% CI, 0.39-0.56] for rDWI). Both quantitative parameters correlated moderately (Pearson R=0.54 [95% CI, 0.46-0.61]; P<0.001, n=367). The interquartile range rDWI SI (n=188), but not the mean rFLAIR SI (n=172), was an independent predictor of excellent functional outcome (odds ratio, 0.67 per 0.1 unit increase of interquartile range rDWI SI, 95% CI, 0.51-0.89, P=0.01). CONCLUSIONS: Agreement between the quantitative and qualitative approach may be insufficient to advocate DWI or FLAIR quantification as alternative for visual rating.

Early effect of thrombolysis on structural brain network organisation after anterior-circulation stroke in the randomized WAKE-UP trial.

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke.

Cognition-Related Functional Topographies in Parkinson's Disease: Localized Loss of the Ventral Default Mode Network.

Cognitive dysfunction in Parkinson's disease (PD) is associated with increased expression of the PD cognition-related pattern (PDCP), which overlaps with the normal default mode network (DMN). Here, we sought to determine the degree to which the former network represents loss of the latter as a manifestation of the disease process. To address this, we first analyzed metabolic images (fluorodeoxyglucose positron emission tomography [PET]) from a large PD sample with varying cognitive performance. Cognitive impairment in these patients correlated with increased PDCP expression as well as DMN loss. We next determined the spatial relationship of the 2 topographies at the subnetwork level. To this end, we analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data from an independent population. This approach uncovered a significant PD cognition-related network that resembled previously identified PET- and rs-fMRI-based PDCP topographies. Further analysis revealed selective loss of the ventral DMN subnetwork (precuneus and posterior cingulate cortex) in PD, whereas the anterior and posterior components were not affected by the disease. Importantly, the PDCP also included a number of non-DMN regions such as the dorsolateral prefrontal and medial temporal cortex. The findings show that the PDCP is a reproducible cognition-related network that is topographically distinct from the normal DMN.

Imaging Markers of Brain Frailty and Outcome in Patients With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke. METHODS: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial (AX200 in Ischemic Stroke Trial), a randomized controlled clinical trial of granulocyte colony-stimulating factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (ie, the brain parenchymal fraction) and total brain volumes from routine baseline magnetic resonance imaging data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces, white matter hyperintensities, lacunes, as well as a small vessel disease burden, were rated visually. Functional outcomes (modified Rankin Scale score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes. RESULTS: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased brain parenchymal fraction was associated with higher odds of excellent outcome (odds ratio per percent increase, 1.078 [95% CI, 1.008-1.153]). Total brain volumes and small vessel disease burden were not associated with functional outcome. An interaction between brain parenchymal fraction and large vessel occlusion on excellent outcome was not observed. CONCLUSIONS: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00927836.

Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.

BACKGROUND AND PURPOSE: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke). METHODS: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE. RESULTS: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], P<0.001). Higher age (P=0.04) and male sex (P=0.01) were predictors for the occurrence of SAE. CONCLUSIONS: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function. Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26). Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Sonothrombolysis in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials. METHODS: We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time. RESULTS: We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03-4.54]; adjusted OR, 2.33 [95% CI, 1.02-5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68-6.11]; adjusted OR, 2.55 [95% CI, 0.76-8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented. CONCLUSIONS: Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

A novel approach for assessing hypoperfusion in stroke using spatial independent component analysis of resting-state fMRI.

Individualized treatment of acute stroke depends on the timely detection of ischemia and potentially salvageable tissue in the brain. Using functional MRI (fMRI), it is possible to characterize cerebral blood flow from blood-oxygen-level-dependent (BOLD) signals without the administration of exogenous contrast agents. In this study, we applied spatial independent component analysis to resting-state fMRI data of 37 stroke patients scanned within 24 hr of symptom onset, 17 of whom received follow-up scans the next day. Our analysis revealed "Hypoperfusion spatially-Independent Components" (HICs) whose spatial patterns of BOLD signal resembled regions of delayed perfusion depicted by dynamic susceptibility contrast MRI. These HICs were detected even in the presence of excessive patient motion, and disappeared following successful tissue reperfusion. The unique spatial and temporal features of HICs allowed them to be distinguished with high accuracy from other components in a user-independent manner (area under the curve = 0.93, balanced accuracy = 0.90, sensitivity = 1.00, and specificity = 0.85). Our study therefore presents a new, noninvasive method for assessing blood flow in acute stroke that minimizes interpretative subjectivity and is robust to severe patient motion.

Different Mismatch Concepts for Magnetic Resonance Imaging-Guided Thrombolysis in Unknown Onset Stroke.

OBJECTIVE: To explore the prevalence of the perfusion-weighted imaging (PWI)-diffusion-weighted imaging (DWI) mismatch and response to intravenous thrombolysis in the WAKE-UP trial. METHODS: We performed a prespecified post hoc analysis of ischemic stroke patients screened for DWI-fluid-attenuated inversion recovery (FLAIR) mismatch in WAKE-UP who underwent PWI. We defined PWI-DWI mismatch as ischemic core volume < 70ml, mismatch volume > 10ml, and mismatch ratio > 1.2. Primary efficacy end point was a modified Rankin Scale score of 0-1 at 90 days, adjusted for age and symptom severity. RESULTS: Of 1,362 magnetic resonance imaging-screened patients, 431 underwent PWI. Of these, 57 (13%) had a double mismatch, 151 (35%) only a DWI-FLAIR mismatch, and 54 (13%) only a PWI-DWI mismatch. DWI-FLAIR mismatch was more prevalent than PWI-DWI mismatch (48%, 95% confidence interval [CI] = 43-53% vs 26%, 95% CI = 22-30%; p < 0.0001). Screening for either one of the mismatch profiles resulted in a yield of 61% (95% CI = 56-65%). Prevalence of PWI-DWI mismatch was similar in patients with (27%) or without (24%) DWI-FLAIR mismatch (p = 0.52). In an exploratory analysis in the small subgroup of 208 randomized patients with PWI, PWI-DWI mismatch status did not modify the treatment response (p for interaction = 0.73). INTERPRETATION: Evaluating both the DWI-FLAIR and PWI-DWI mismatch patterns in patients with unknown time of stroke onset will result in the highest yield of thrombolysis treatment. The treatment benefit of alteplase in patients with a DWI-FLAIR mismatch seems to be driven not merely by the presence of a PWI-DWI mismatch, although this analysis was underpowered. ANN NEUROL 2020;87:931-938.

Effect of intravenous alteplase on post-stroke depression in the WAKE UP trial.

BACKGROUND AND PURPOSE: The aim was to study the effect of intravenous alteplase on the development of post-stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD. METHODS: This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290), in whom a composite end-point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90 days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale. RESULTS: Information on the composite end-point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43-0.94; p = 0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS. CONCLUSIONS: Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90 days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD.

Cost-Effectiveness of Magnetic Resonance Imaging-Guided Thrombolysis for Patients With Stroke With Unknown Time of Onset.

OBJECTIVES: Patients waking up with stroke symptoms are often excluded from intravenous thrombolysis with alteplase (IV-tpa). The WAKE-UP trial, a European multicenter randomized controlled trial, proved the clinical effectiveness of magnetic resonance imaging-guided IV-tpa for these patients. This analysis aimed to assess the cost-effectiveness of the intervention compared to placebo. METHODS: A Markov model was designed to analyze the cost-effectiveness over a 25-year time horizon. The model consisted of an inpatient acute care phase and a rest-of-life phase. Health states were defined by the modified Rankin Scale (mRS). Initial transition probabilities to mRS scores were based on WAKE-UP data and health state utilities on literature search. Costs were based on data from the University Medical Center Hamburg-Eppendorf, literature, and expert opinion. Incremental costs and effects over the patients' lifetime were estimated. The analysis was conducted from a formal German healthcare perspective. Univariate and probabilistic sensitivity analyses were performed. RESULTS: Treatment with IV-tpa resulted in cost savings of €51 009 and 1.30 incremental gains in quality-adjusted life-years at a 5% discount rate. Univariate sensitivity analysis revealed incremental cost-effectiveness ratio being sensitive to the relative risk of favorable outcome on mRS for placebo patients after stroke, the costs of long-term care for patients with mRS 4, and patient age at initial stroke event. In all cases, IV-tpa remained cost-effective. Probabilistic sensitivity analysis proved IV-tpa cost-effective in >95% of the simulations results. CONCLUSIONS: Magnetic resonance imaging-guided IV-tpa compared to placebo is cost-effective in patients with ischemic stroke with unknown time of onset.